The present invention relates to new substituted aryl and heteroaryl derivatives of general formula
Arxe2x80x94Axe2x80x94(HCR1)xe2x80x94Xxe2x80x94Y,xe2x80x83xe2x80x83(I)
the tautomers, the stereoisomers, the mixtures thereof and the salts thereof, particularly the physiologically acceptable salts with inorganic or organic acids or bases which have valuable properties.
The compounds of the above general formula I wherein Y does not contain a cyano group, have valuable pharmacological properties, particularly an antithrombotic activity, and
the compounds of the above general formula I wherein Y contains a cyano group, are valuable intermediate products for preparing the compounds of general formula I wherein R5 denotes an optionally substituted amino-C1-3-alkyl, amidino, guanidino or guanidino-C1-3-alkyl group.
The present invention thus relates to the new compounds of the above general formula I and the preparation thereof, the pharmaceutical compositions containing the pharmacologically active compounds and their use.
In the above general formula
A denotes an ethynylene group, a vinylene or ethylene group optionally substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group or by a chlorine, bromine or iodine atom,
R1 denotes a hydrogen atom, a C1-3-alkyl or carboxy-C1-3-alkyl group,
Ar denotes a phenyl group substituted by the groups R2 to R4, wherein
R2 denotes
a C1-6-alkyl- or C3-7-cycloalkyl-C1-3-alkyl group, which may be substituted in the C1-6- and C1-3-alkyl moieties by a carboxy, phenyl, amino, C1-3-alkylamino, carboxy-C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-(carboxy-C1-3-alkyl)-C1-3-alkylamino, C3-7-cycloalkylamino, phenylamino, Nxe2x80x94(C1-3-alkyl)-phenylamino, Nxe2x80x94(C1-4-alkanoyl)-phenylamino, heteroarylamino, Nxe2x80x94(C1-3-alkyl)-heteroarylamino, N-(carboxy-C1-3-alkyl)-phenylamino or N-(carboxy-C1-3-alkyl)-heteroarylamino group,
a carboxy-C1-5-alkyl group which is substituted in the alkyl moiety by a C1-3-alkylamino, N,N-di-(C1-3-alkyl)-amino, pyrrolidino, piperidino or hexamethyleneimino group,
a carboxy-C1-5-alkyl group wherein the hydrogen atoms of a methylene group are replaced by a n-C2-5-alkylene bridge,
a phenyl, phenyloxy or phenylsulphonyl group, which may be substituted in each case in the phenyl moiety by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, carboxy-C1-3-alkyl or C1-3-alkoxy group,
a C1-5-alkylamino, carboxy-C1-3-alkylamino, di-(C1-5-alkyl)-amino, N-(carboxy-C1-3-alkyl)-C1-5-alkylamino, C3-7-cycloalkylamino, N-(carboxy-C1-3-alkyl)-C3-7-cycloalkylamino, phenylamino, Nxe2x80x94(C1-3-alkyl)-phenylamino, N-(carboxy-C1-3-alkyl)-phenylamino, heteroarylamino, Nxe2x80x94(C1-3-alkyl)-heteroarylamino or N-(carboxy-C1-3-alkyl)-heteroarylamino group,
a C1-5-alkylcarbonylamino, C3-7-cycloalkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C1-5-alkylsulphonylamino, arylsulphonylamino, heteroarylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-C1-5-alkylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-C3-7-cycloalkylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-arylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-heteroarylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-C1-5-alkylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-arylsulphonylamino or Nxe2x80x94(C1-3-alkyl)-heteroarylsulphonylamino group, whilst
the above-mentioned Nxe2x80x94(C1-3-alkyl) moieties may additionally be substituted by a carboxy, carboxy-C1-3-alkylaminocarbonyl or Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylaminocarbonyl group or, with the exception of the xcex1-carbon atom in relation to the nitrogen atom, by a hydroxy, carboxy-C1-3-alkoxy, amino, carboxy-C1-3-alkylamino or Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino group,
a 5- to 7-membered cycloalkyleneimino group,
an amino, C1-5-alkylamino, C3-7-cycloalkylamino, arylamino, aryl-C1-3-alkylamino, heteroarylamino or heteroaryl-C1-3-alkyl-amino group, which are substituted in each case at the amino nitrogen atom by a C1-3-alkylcarbonyl, carboxy-C1-3-alkylcarbonyl, carboxy-C1-3-alkylaminocarbonyl, 2-oxo-pyrrolidinylcarbonyl or piperazinocarbonyl group, whilst additionally
(i) the above-mentioned amino group, which is monosubstituted by a C1-3-alkylcarbonyl, carboxy-C1-3-alkylcarbonyl or carboxy-C1-3-alkylaminocarbonyl group, is substituted by a 5- to 7-membered cycloalkyleneimino group or by a N,N-di-(C1-5-alkyl)-amino group, and
(ii) the alkyl moiety of the above-mentioned C1-3-alkylcarbonyl group is substituted by a carboxy, amino, hydroxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylaminocarbonyl, carboxy-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino or amino-C1-3-alkylcarbonylamino group or by a carboxy or hydroxy group and by an amino or trifluoroacetylamino group,
a carbimino group which is substituted at the nitrogen atom by a carboxy-C1-3-alkoxy, amino, C1-3-alkylamino, carboxy-C1-3-alkylamino, di-(C1-3-alkyl)-amino or N-(carboxy-C1-3-alkyl)-C1-3-alkylamino group and at the carbon atom by a C1-5-alkyl group, by a phenyl group optionally substituted by a C1-3-alkyl or C1-3-alkoxy group or by a heteroaryl group optionally substituted by a C1-3-alkyl group,
a heteroaryl or heteroaryl-C1-3-alkyl group, which may in each case additionally be substituted in the heteroaryl moiety by a phenyl or heteroaryl group or by a phenyl or heteroaryl group and by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group,
a 5-oxo-4,5-dihydro-pyrazolyl or 6-oxo-4,5-dihydro-pyridazinyl group optionally substituted by 1 to 3 C1-3-alkyl groups wherein an alkyl substituent may at the same time be substituted by a carboxy or C1-3-alkoxycarbonyl group, or
a carbonyl group which is substituted
by a hydrogen atom, by a hydroxy, C1-5-alkoxy or C3-7-cycloalkoxy group,
by a C1-5-alkyl or C3-7-cycloalkyl group optionally substituted by a carboxy group,
by a C1-3-alkyl group substituted by a piperazino group,
by a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkoxy or carboxy group,
by an amino, C1-5-alkylamino, carboxy-C1-3-alkylamino, C3-7-cycloalkylamino, phenylamino or heteroarylamino group, each of which may additionally be substituted at the amino nitrogen atom by a C1-5-alkyl, C3-7-Cycloalkyl, phenyl-C1-3-alkyl, carboxy-C1-3-alkyl, 2-[di-(C1-3-alkyl)-amino]-ethyl, 3-[di-(C1-3-alkyl)-amino]-propyl, di-(C1-3-alkyl)-amino, 2-(N-carboxy-C1-3-alkyl-C1-3-alkylamino)-ethyl, 3-(N-carboxy-C1-3-alkyl-C1-3-alkylamino)-propyl or N-carboxy-C1-3-alkyl-C1-3-alkylamino, phenyl, pyridyl, pyrrolidinyl or piperidinyl group,
by a pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group optionally substituted by one or two C1-3-alkyl groups onto which a phenyl ring may be fused via two adjacent carbon atoms,
by a C3-6-cycloalkyleneimino, C5-8-bicycloalkyleneimino, morpholino, piperazino, dihydropyrazolo, tetrahydropyrazolo, tetrahydroisoxazolo, tetrahydropyrazinyl or tetrahydropyridazinyl group optionally substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group or
by a C3-6-cycloalkyleneimino group optionally substituted by a C1-3-alkyl, carboxy-C1-3-alkyl, hydroxy, hydroxy-C1-3-alkyl, amino, carboxy, carboxy-C1-3-alkoxy-C1-3-alkyl, carboxy-C1-3-alkylamino-C1-3-alkyl or carboxy-C1-3-alkylaminocarbonyl-C1-3-alkyl group,
by a C5-8-bicycloalkyleneimino, morpholino, piperazino, dihydropyrazolo, tetrahydropyrazolo, tetrahydroisoxazolo, tetrahydropyrazinyl or tetrahydropyridazinyl group optionally substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group,
R3 denotes
a hydrogen, fluorine, chlorine, bromine or iodine atom, a formyl or trifluoromethyl group,
a C1-3-alkoxy, amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-4-alkanoylamino or Nxe2x80x94(C1-4-alkanoyl)-C1-3-alkylamino group,
a C1-3-alkyl group optionally substituted by a hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino or carboxy-C1-3-alkylaminocarbonyl group,
a C2-3-alkenyl group substituted by a carboxy or carboxy-C1-3-alkylaminocarbonyl group or
a carbimino group optionally substituted at the carbon atom by a C1-3-alkyl group, which is substituted at the imino nitrogen atom by a carboxy-C1-3-alkoxy or aminocarbonylamino group,
or R2 and R3 together denote a xe2x80x94COxe2x80x94Oxe2x80x94CH2xe2x80x94 or xe2x80x94COxe2x80x94Oxe2x80x94CH2CH2xe2x80x94 group and
R4 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom, a C1-3-alkyl, C3-7-cycloalkyl, trifluoromethyl or C1-3-alkoxy group,
or Ar may also denote a heteroaryl group which may be substituted by the above-mentioned groups R2 to R4, which are as hereinbefore defined,
X denotes an oxygen or sulphur atom, a methylene group, a carbonyl, sulphinyl, sulphonyl, imino, Nxe2x80x94(C1-3-alkyl)-imino or N-(carboxy-C1-3-alkyl)-imino group optionally substituted by one or two C1-3-alkyl groups, whilst the alkyl moiety of the Nxe2x80x94(C1-3-alkyl)-imino group may additionally be substituted in the 2- or 3-position by an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-4-alkanoylamino or Nxe2x80x94(C1-4-alkanoyl)-C1-3-alkylamino group, and
Y denotes a cyclohexyl group substituted by an amino group or a phenyl or heteroaryl group substituted by the group R5, whilst the above-mentioned phenyl group may be substituted in each case by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl or C1-3-alkoxy group and the above-mentioned heteroaryl group may be substituted by a C1-3-alkyl group and
R5 denotes a hydrogen atom, a cyano group or an amino, amino-C1-3-alkyl, amidino, guanidino or guanidino-C1-3-alkyl group optionally substituted by a group which may be cleaved in vivo.
By the above-mentioned heteroaryl groups is meant a 5-membered heteroaromatic group optionally substituted by one or two C1-3-alkyl groups which contains an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom or an imino group optionally substituted by a C1-3-alkyl group, an oxygen or sulphur atom and one or two nitrogen atoms and the partially hydrogenated derivatives thereof, particularly the dihydro derivatives thereof, or a 6-membered heteroaromatic group which contains one, two or three nitrogen atoms, whilst additionally a phenyl ring may be fused to the above-mentioned 5- and 6-membered heteroaromatic rings via two adjacent carbon atoms.
Moreover, the carboxy groups mentioned in the above definitions of the groups may be replaced by a tetrazolyl group or by a group which can be converted in vivo into a carboxy group, e.g. by a hydroxymethyl or formyl group, by a carboxy group esterified with an alcohol wherein the alcoholic moiety is preferably a C1-6-alkanol, a phenyl-C1-3-alkanol, a C3-9-cycloalkanol, whilst a C5-8-cycloalkanol may additionally be substituted by one or two C1-3-alkyl groups, a C5-8-cycloalkanol, wherein a methylene group in the 3- or 4-position is replaced by an oxygen atom or by an imino group optionally substituted by a C1-3-alkyl, phenyl-C1-3-alkyl, phenyl-C1-3-alkoxycarbonyl or C2-6-alkoxycarbonyl or C2-6-alkanoyl group and the cycloalkanol moiety may additionally be substituted by one or two C1-3-alkyl groups, a C4-7-cycloalkenol, a C3-5-alkenol, a phenyl-C3-5-alkenol, a C3-5-alkynol or phenyl-C3-5-alkynol with the proviso that no bond to the oxygen atom starts from a carbon atom which carries a double or triple bond, a C3-8-cycloalkyl-C1-3-alkanol, a bicycloalkanol with a total of 8 to 10 carbon atoms which is additionally substituted by one or two C1-3-alkyl groups in the bicycloalkyl moiety, a 1,3-dihydro-oxo-1-isobenzofuranol or an alcohol of formula
RaCOxe2x80x94Oxe2x80x94(RbCRc)xe2x80x94OH,
wherein
Ra denotes a C1-8-alkyl, C5-7-cycloalkyl, phenyl or phenyl-C1-3-alkyl group,
Rb denotes a hydrogen atom, a C1-3-alkyl, C5-7-cycloalkyl or phenyl group and
Rc denotes a hydrogen atom or a C1-3-alkyl group,
and the imino or amino groups mentioned in the definition of the groups may be substituted by a group which can be cleaved in vivo, e.g. by a hydroxy group, by an acyl group such as the benzoyl or pyridinoyl group or a C1-16-alkanoyl group such as the formyl, acetyl, propionyl, butanoyl, pentanoyl or hexanoyl group, by an allyloxycarbonyl group, by a C1-16-alkoxycarbonyl group such as the methyloxycarbonyl, ethyloxycarbonyl, propyloxycarbonyl, isopropyloxcarbonyl, butyloxycarbonyl, tert-butyloxycarbonyl, pentyloxycarbonyl, hexyloxycarbonyl, octyloxycarbonyl, nonyloxycarbonyl, decyloxycarbonyl, undecyloxycarbonyl, dodecyloxycarbonyl or hexadecyloxycarbonyl group, by a phenyl-C1-16-alkoxycarbonyl group such as the benzyloxycarbonyl, phenylethyloxycarbonyl or phenylpropyloxycarbonyl group, by a C1-3-alkylsulphonyl-C2-4-alkoxycarbonyl, C1-3-alkoxy-C2-4-alkoxy-C2-4-alkoxycarbonyl or RaCOxe2x80x94Oxe2x80x94(RbCRc)xe2x80x94Oxe2x80x94CO-group, wherein Ra to Rb are as hereinbefore defined.
Moreover, the saturated alkyl and alkoxy moieties which contain more than 2 carbon atoms, as well as the alkanoyl and unsaturated alkyl moieties which contain more than 3 carbon atoms in the above-mentioned definitions also include the branched isomers thereof such as, for example, the isopropyl, tert-butyl, isobutyl group, etc.
Preferred compounds of general formula I of the present invention are those wherein
A denotes an ethynylene group, a vinylene or ethylene group optionally substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group or by a chlorine, bromine or iodine atom,
R1 denotes a hydrogen atom, a C1-3-alkyl or carboxy-C1-3-alkyl group,
Ar denotes a phenyl group substituted by the groups R2 to R4, whilst
R2 denotes
a C1-3-alkyl group which may be substituted by a carboxy, phenyl, amino, C1-3-alkylamino, carboxy-C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-(carboxy-C1-3-alkyl)-C1-3-alkylamino, phenylamino, Nxe2x80x94(C1-3-alkyl)-phenylamino, Nxe2x80x94(C1-4-alkanoyl)-phenylamino, heteroarylamino, Nxe2x80x94(C1-3-alkyl)-heteroarylamino, N-(carboxy-C1-3-alkyl)-phenylamino or N-(carboxy-C1-3-alkyl)-heteroarylamino group,
a phenyl or phenylsulphonyl group, which may be substituted in each case in the phenyl moiety by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, carboxy-C1-3-alkyl or C1-3-alkoxy group,
a C1-3-alkylamino, carboxy-C1-3-alkylamino, di-(C1-3-alkyl)-amino, N-(carboxy-C1-3-alkyl)-C1-3-alkylamino, phenylamino, Nxe2x80x94(C1-3-alkyl)-phenylamino, N-(carboxy-C1-3-alkyl)-phenylamino, heteroarylamino, Nxe2x80x94(C1-3-alkyl)-heteroarylamino or N-(carboxy-C1-3-alkyl)-heteroarylamino group,
a C1-5-alkylcarbonylamino, arylcarbonylamino, heteroarylcarbonylamino, C1-5-alkylsulphonylamino, arylsulphonylamino, heteroarylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-C1-5-alkylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-arylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-heteroarylcarbonylamino, Nxe2x80x94(C1-3-alkyl)-C1-5-alkylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-arylsulphonylamino, Nxe2x80x94(C1-3-alkyl)-heteroarylsulphonylamino, N-(carboxy-C1-3-alkyl)-C1-5-alkylcarbonylamino, N-(carboxy-C1-3-alkyl)-arylcarbonylamino, N-(carboxy-C1-3-alkyl)-heteroarylcarbonylamino, N-(carboxy-C3-alkyl)-C1-5-alkylsulphonylamino, N-(carboxy-C1-3-alkyl)-aryisulphonylamino or N-(carboxy-C1-3-alkyl)-heteroarylsulphonylamino group,
a carbimino group which is substituted at the nitrogen atom by a carboxy-C1-3-alkoxy, amino, C1-3-alkylamino, carboxy-C1-3-alkylamino, di-(C1-3-alkyl)-amino or N-(carboxy-C1-3-alkyl)-C1-3-alkylamino group and at the carbon atom by a C1-5-alkyl group, by a phenyl group optionally substituted by a C1-3-alkyl or C1-3-alkoxy group or by a heteroaryl group optionally substituted by a C1-3-alkyl group,
a heteroaryl or heteroaryl-C1-3-alkyl group, which may in each case additionally be substituted in the heteroaryl moiety by a phenyl or heteroaryl group or by a phenyl or heteroaryl group and by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group, or
a carbonyl group which is substituted
by a hydrogen atom, by a hydroxy, C1-5-alkoxy or C3-7-cycloalkoxy group,
by a C1-5-alkyl or C3-7-cycloalkyl group optionally substituted by a carboxy group,
by a phenyl group which may be substituted by a fluorine, chlorine, bromine or iodine atom, by a C1-3-alkyl, carboxy-C1-3-alkyl, C1-3-alkoxy or carboxy group,
by an amino, C1-5-alkylamino, C3-7-cycloalkylamino, phenylamino or heteroarylamino group, each of which may additionally be substituted at the amino nitrogen atom by a C1-5-alkyl, C5-7-cycloalkyl, phenyl-C1-3-alkyl, carboxy-C1-3-alkyl, 2-[di-(C1-3-alkyl)-amino]-ethyl, 3-[di-(C1-3-alkyl)-amino]-propyl, di-(C1-3-alkyl)-amino, 2-(N-carboxy-C1-3-alkyl-C1-3-alkylamino)-ethyl, 3-(N-carboxy-C1-3-alkyl-C1-3-alkylamino)-propyl or N-carboxy-C1-3-alkyl-C1-3-alkylamino, pyrrolidinyl or piperidinyl group,
by a pyrrolyl, thienyl, imidazolyl, pyrazolyl, thiazolyl, pyridinyl, pyrimidinyl, pyrazinyl or pyridazinyl group optionally substituted by a C1-3-alkyl group, onto which a phenyl ring may be fused via two adjacent carbon atoms,
by a C3-6-cycloalkyleneimino, C5-8-bicycloalkyleneimino, morpholino, piperazino, dihydropyrazolo, tetrahydropyrazolo, tetrahydroisoxazolo, tetrahydropyrazinyl or tetrahydropyridazinyl group optionally substituted by a C1-3-alkyl or carboxy-C1-3-alkyl group or
by a pyrrolidino group, whilst the above-mentioned pyrrolidino group is substituted by a hydroxy, hydroxy-C1-3-alkyl, amino, carboxy, carboxy-C1-3-alkyl, carboxy-C1-3-alkoxy-C1-3-alkyl, carboxy-C1-3-alkylamino-C1-3-alkyl or carboxy-C1-3-alkylaminocarbonyl-C1-3-alkyl group,
R3 denotes
a hydrogen atom or a formyl group,
an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-4-alkanoylamino or Nxe2x80x94(C1-4-alkanoyl)-C1-3-alkylamino group,
a C1-3-alkyl group optionally substituted by a hydroxy, C1-3-alkoxy, carboxy, carboxy-C1-3-alkoxy, carboxy-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino or carboxy-C1-3-alkylaminocarbonyl group,
a C2-3-alkenyl group substituted by a carboxy or carboxy-C1-3-alkylaminocarbonyl group or
a carbimino group optionally substituted at the carbon atom by a C1-3-alkyl group, which is substituted at the imino nitrogen atom by a carboxy-C1-3-alkoxy or aminocarbonylamino group,
or R2 and R3 together denote a xe2x80x94COxe2x80x94Oxe2x80x94CH2 or xe2x80x94COxe2x80x94Oxe2x80x94CH2CH2xe2x80x94 group and
R4 denotes a hydrogen, fluorine, chlorine, bromine or iodine atom or a C1-3-alkyl, C3-7-cycloalkyl or C1-3-alkoxy group,
or Ar also denotes a heteroaryl group which may be substituted by the abovementioned groups R2 to R4,
X denotes an oxygen or sulphur atom, a methylene group optionally substituted by one or two C1-3-alkyl groups, a carbonyl, sulphinyl, sulphonyl, imino, Nxe2x80x94(C1-3-alkyl)-imino or N-(carboxy-C1-3-alkyl)-imino group, whilst the alkyl moiety of the Nxe2x80x94(C1-3-alkyl)-imino group in 2- or 3-position may additionally be substituted by an amino, C1-3-alkylamino, di-(C1-3-alkyl)-amino, C1-4-alkanoylamino or Nxe2x80x94(C1-4-alkanoyl)-C1-3-alkylamino group, and
Y denotes a cyclohexyl group substituted by an amino group or a phenyl or heteroaryl group substituted by the group R5, whilst the above-mentioned phenyl group may be substituted in each case by a fluorine, chlorine, bromine or iodine atom or by a C1-3-alkyl or C1-3-alkoxy group and the above-mentioned heteroaryl group may be substituted by a C1-3-alkyl group and
R5 denotes a hydrogen atom, a cyano group or an amino, amino-C1-3-alkyl, amidino, guanidino or guanidino-C1-3-alkyl group optionally substituted by a group which can be cleaved in vivo,
the prodrugs thereof, the tautomers, the stereoisomers, the mixtures thereof and the salts thereof,
but particularly those wherein
A denotes a vinylene group optionally substituted by a chlorine, bromine or iodine atom, or an ethylene or ethynylene group,
R1 denotes a hydrogen atom or a C1-3-alkyl group,
Ar denotes a pyridyl or thienyl group substituted by a benzoyl group,
a bromofuranyl group substituted by a pyrrolidinocarbonyl group or
a phenyl group substituted by the groups R2 to R4, whilst
R2 denotes
a phenyl or phenoxy group,
a C1-3-alkyl group which may be substituted by a phenyl, phenylamino, Nxe2x80x94(C1-3-alkyl)-phenylamino or Nxe2x80x94(C1-3-alkanoyl)-phenylamino group,
a carboxy or C1-3-alkoxycarbonyl group,
a benzoyl or phenylsulphonyl group wherein in each case the phenyl moiety may additionally be substituted by a fluorine, chlorine or bromine atom, by a methyl, methoxy, carboxy or C1-3-alkoxycarbonyl group, whilst in the above-mentioned benzoyl groups the oxygen atom may additionally be replaced by a carboxy-C1-3-alkoxyimino or C1-3-alkoxycarbonyl-C1-3-alkoxyimino group,
a C1-5-alkylamino group which may be substituted in the alkyl moiety by a phenyl, carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkylaminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylaminocarbonyl or Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, or a C3-7-cycloalkylamino group, whilst the above-mentioned groups may each additionally be substituted at the amino nitrogen atom by a C3-7-cycloalkanoyl, benzoyl or phenylsulphonyl group, by a carboxy-C1-3-alkylcarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylcarbonyl group wherein the alkyl moiety of the alkylcarbonyl group is substituted in each case by an amino or trifluoroacetylamino group, by a C2-4-alkanoyl group, which may be substituted in the alkanoyl moiety by an amino, carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkoxy, C1-3-alkoxycarbonyl-C1-3-alkoxy, carboxy-C1-3-alkylaminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylaminocarbonyl or Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group, by a carboxy-C1-2-alkylaminocarbonyl, C1-3-alkoxycarbonyl-C1-2-alkylaminocarbonyl, carboxy-C1-3-alkylaminocarbonyl-C1-2-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl-C1-2-alkylaminocarbonyl group,
a formyl, pyridylcarbonyl, thienylcarbonyl, imidazolylcarbonyl, 1-methyl-imidazolylcarbonyl, thiazolylcarbonyl or indolylcarbonyl group,
a benzimidazol-1-yl, benzimidazol-1-yl-methyl or 5-oxo4,5-dihydro-pyrazol-3-yl group optionally substituted by 1 or 2 methyl groups,
a pyrazol-1-yl group substituted by a phenyl group, by a phenyl group and a C1-4-alkyl group or by one or two C1-4-alkyl groups wherein an alkyl substituent may at the same time be substituted by a carboxy or C1-3-alkoxycarbonyl group, or
a carbonyl group which is substituted
by a C1-5-alkyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group,
by a C3-7-cycloalkyl group,
by an amino or C1-5-alkylamino group, which are in each case substituted at the amino nitrogen atom by a C1-3-alkyl group which may be substituted by a C3-7-cycloalkyl, phenyl, pyrrolidinyl or pyridinyl group or in the 2 or 3 position by a di-(C1-3-alkyl)-amino group, or by a di-(C1-3-alkyl)-amino group,
by a carboxy-C1-3-alkylamino or C1-3-alkoxycarbonyl-C1-3-alkylamino group which is in each case substituted at the amino nitrogen atom by a pyrazolyl group optionally substituted by a C1-3-alkyl group,
by a 3- to 7-membered cycloalkyleneimino group which may be substituted by one or two C1-3-alkyl groups, whilst the above-mentioned pyrrolidino groups optionally substituted by a methyl group may additionally be substituted by a hydroxymethyl, carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyl, carboxy-C1-3-alkyloxy-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkyloxy-C1-3-alkyl, carboxy-C1-3-alkylamino-C1-3-alkyl, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino-C1-3-alkyl, C1-3-alkoxycarbonyl-C1-3-alkylamino-C1-3-alkyl, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino-C1-3-alkyl or Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylamino-C1-3-alkyl group,
by a morpholino, piperazino, 4-methyl-piperazino, piperazino-C1-3-alkyl, dihydropyrazolo, tetrahydropyrazolo, tetrahydroisoxazolo or 7-azabicycloheptyl group or
by an Nxe2x80x94(C1-3-alkyl)-phenyl or Nxe2x80x94(C1-3-alkyl)-pyridylamino group optionally substituted in the alkyl moiety by a carboxy or C1-3-alkoxycarbonyl group,
R3 denotes
a hydrogen, fluorine, chlorine or bromine atom,
a hydroxy, C1-3-alkoxy, trifluoromethyl, amino or C2-3-alkanoylamino group,
a C1-3-alkyl group which may be substituted by a hydroxy, carboxy, C1-3-alkoxycarbonyl, carboxy-C1-3-alkoxy, C1-3-alkoxycarbonyl-C1-3-alkoxy, carboxy-C1-3-alkylaminocarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylaminocarbonyl or Nxe2x80x94(C1-3-alkyl)-C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group,
a C1-3-alkyl group which is substituted by a carboxy-C1-3-alkylamino, C1-3-alkoxycarbonyl-C1-3-alkylamino, Nxe2x80x94(C1-3-alkyl)-carboxy-C1-3-alkylamino or C1-3-alkoxycarbonyl-C1-3-alkylaminocarbonyl group,
a C2-3-alkenyl group substituted by a carboxy or C1-3-alkoxycarbonyl group or a carbimino group optionally substituted at the carbon atom by a C1-3-alkyl group, which is substituted at the imino nitrogen atom by a carboxy-C1-3-alkoxy, C1-3-alkoxycarbonyl-C1-3-alkoxy or aminocarbonylamino group,
or R2 and R3 together denote a xe2x80x94COxe2x80x94Oxe2x80x94CH2-group and
R4 denotes a hydrogen, fluorine, chlorine or bromine atom, a C1-3-alkyl or trifluoromethyl group,
X denotes an oxygen or sulphur atom or an xe2x80x94NH-group optionally substituted by a C1-3-alkyl group and
Y denotes a cyclohexyl group substituted by an amino group, a phenylene or pyridinylene group substituted by an amidino group, which may be substituted by a benzoyl or C1-8-alkoxycarbonyl group, whilst the above-mentioned phenylene group may be substituted by a methyl or methoxy group and the above-mentioned pyridinylene group may be substituted by a methyl group,
the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Particularly preferred compounds of the present invention are the compounds of general formula 
wherein
A denotes an ethylene or ethynylene group,
X denotes an oxygen atom or an imino group optionally substituted by a methyl group,
R2 denotes
a C1-4-alkylcarbonylamino or C3-5-cycloalkylcarbonylamino group, which is substituted in each case at the amino nitrogen atom by a carboxy-C1-2-alkyl, C1-3-alkoxycarbonyl-C1-2-alkyl, carboxy-C1-2-alkylaminocarbonyl-C1-2-alkyl or C3-alkoxycarbonyl-C1-2-alkylaminocarbonyl-C1-2-alkyl group,
a C1-4-alkylamino or C3-5-cycloalkylamino group, which is substituted in each case at the amino nitrogen atom by a carboxy-C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl-C3-alkylcarbonyl, carboxy-C1-2-alkylaminocarbonyl-C1-2-alkylcarbonyl, C1-3-alkoxy-carbonyl-C1-2-alkylaminocarbonyl-C1-2-alkylcarbonyl, carboxy-C1-2-alkylaminocarbonyl, C1-3-alkoxycarbonyl-C1-2-alkylaminocarbonyl, carboxy-C1-2-alkylaminocarbonyl-C1-2-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-2-alkylaminocarbonyl-C1-2-alkylaminocarbonyl group optionally substituted in the alkyl moiety by an amino group, or by a carboxymethyloxymethylcarbonyl, C1-3-alkoxycarbonyl-methyloxymethylcarbonyl, carboxymethylaminomethylcarbonyl, C1-3-alkoxycarbonyl-methylaminomethylcarbonyl, N-methyl-carboxymethylaminomethylcarbonyl, N-methyl-C1-3-alkoxycarbonyl-carboxymethylaminomethylcarbonyl, aminomethylcarbonyl, 2-amino-ethylcarbonyl, carboxy-C1-2-alkylaminocarbonylmethyloxymethylcarbonyl, C1-3-alkoxycarbonyl-C1-2-alkylaminocarbonylmethyloxymethylcarbonyl, carboxy-C1-2-alkylaminocarbonylmethylaminomethylcarbonyl, C1-3-alkoxycarbonyl-C1-2-alkylaminocarbonylmethylaminomethylcarbonyl, N-methyl-carboxy-C1-2-alkylaminocarbonylmethylaminomethylcarbonyl or N-methyl-C1-3-alkoxycarbonyl-C1-2-alkylaminocarbonylmethylaminomethylcarbonyl group, or
a carbonyl group which is substituted
by a cyclopentyl group,
by a C3-5-alkyl group which may additionally be substituted by a carboxy or C1-3-alkoxycarbonyl group,
by a C1-4-alkylamino, phenylamino or pyridylamino group substituted at the amino nitrogen atom by a C1-4-alkyl, carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group,
by a pyrrolidino group substituted by a methyl, hydroxymethyl, amino, carboxy, C1-3-alkoxycarbonyl, carboxy-C1-2-alkyl, C1-3-alkoxycarbonyl-C1-2-alkyl, carboxymethyloxymethyl, C1-3-alkoxycarbonylmethyloxymethyl, carboxymethylaminomethyl, C1-3-alkoxycarbonyl-methylaminomethyl, carboxymethylaminocarbonylmethyloxymethyl or C1-3-alkoxycarbonylmethylaminocarbonylmethyloxymethyl group,
R3 denotes
a hydrogen, fluorine, chlorine or bromine atom or a trifluoromethyl group,
a C1-2-alkyl group optionally substituted by a hydroxy, carboxy, C1-3-alkoxycarbonyl, carboxymethyloxy, C1-3-alkoxycarbonyl-methyloxy, carboxymethylamino, N-methyl-carboxymethylamino, C1-3-alkoxycarbonylmethylamino, N-methyl-C1-3-alkoxycarbonylmethylamino, carboxymethylaminocarbonyl or C1-3-alkoxycarbonylmethylaminocarbonyl group,
a vinyl group substituted by a carboxy or C1-3-alkoxycarbonyl group,
R4 denotes a hydrogen, fluorine, chlorine or bromine atom, a methyl, ethyl or trifluoromethyl group and
Y denotes an amidino group optionally substituted by a C1-8-alkoxycarbonyl or benzoyl group,
the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
Most particularly preferred compounds of the present invention are the compounds of general formula Ia wherein
A denotes an ethylene or ethynylene group,
X denotes an imino group,
R2 denotes
a C1-4-alkylaminocarbonyl group, which is substituted in each case at the amino nitrogen atom by a carboxy-C1-2-alkyl or C1-3-alkoxycarbonyl-C1-2-alkyl group,
a C1-4-alkylamino group which is substituted at the amino nitrogen atom by a carboxy-C1-3-alkylcarbonyl, C1-3-alkoxycarbonyl-C1-3-alkylearbonyl, carboxy-C1-2-alkylaminocarbonyl or C1-3-alkoxycarbonyl-C1-2-alkylaminocarbonyl group, or
a carbonyl group which is substituted
by a C3-5-alkyl group which may additionally be substituted by a carboxy or C1-3-alkoxycarbonyl group,
by a C1-4-alkylamino or pyridylamino group substituted at the amino nitrogen atom by a carboxy-C1-3-alkyl or C1-3-alkoxycarbonyl-C1-3-alkyl group,
by a pyrrolidino group optionally substituted by a methyl group,
R3 denotes a C1-2-alkyl group optionally substituted by a carboxy or C1-3-alkoxycarbonyl group,
R4 denotes a hydrogen atom or a methyl group and
Y denotes an amidino group optionally substituted by a C1-8-alkoxycarbonyl or benzoyl group,
the tautomers, the stereoisomers, the mixtures thereof and the salts thereof.
The following are mentioned as examples of particularly preferred compounds:
(a) rac-4-{3-[5-ethoxycarbonylmethyl-2-methyl-4-(2-methyl-pyrrolidinocarbonyl)-phenyl]-propargylamino}benzamidine,
(b) rac-4-{3-[2,5-dimethyl-4-(2-methyl-pyrrolidinocarbonyl)-phenyl]-propargylamino}benzamidine,
(c) 4-[3-(2,5-dimethyl-4-isopropylcarbonyl-phenyl)propargyl-amino]benzamidine,
(d) 4-{3-[2,5-dimethyl-4-(N-methyl-N-pyridin-2-yl-aminocarbonyl)-phenyl]propargylamino}benzamidine,
(e) 4-{3-[2,5-dimethyl-4-(N-methyl-N-pyridin-2-yl-aminocarbonyl)-phenyl]prop-1-ylamino}benzamidine,
(f) 4-[3-(3-methyl-4-pyrrolidinocarbonyl-phenyl)-propargyl-amino]-benzamidine,
(g) 4-{3-[2,5-dimethyl-4-(N-(2-methoxycarbonyl-ethyl)-N-ethyl-carbonylamino)-phenyl]-propargylamino}benzamidine,
(h) 4-{3-[2,5-dimethyl-4-(N-isopropyl-N-hydroxycarbonylmethyl-aminocarbonyl-amino)-phenyl]-propargylamino}-benzamidine and
(i) 4-{3-[2,5-dimethyl-4-(N-isopropyl-N-hydroxycarbonylmethyl-carbonyl-amino)-phenyl]-propargylamino}-benzamidine
and the salts thereof.
According to the invention, the compounds of general formula I are prepared by known methods, e.g. by the following methods:
a. reacting a compound of general formula
Arxe2x80x94Z1,xe2x80x83xe2x80x83(II)
xe2x80x83wherein
Ar is as hereinbefore defined and
Z1 denotes a leaving group such as a halogen atom or a sulphonyloxy group, e.g. a chlorine, bromine or iodine atom or a trifluoromethylsulphonyloxy group, with a compound of general formula
Hxe2x80x94Axe2x80x2xe2x80x94HCR1xe2x80x94Xxe2x80x94Yxe2x80x2,xe2x80x83xe2x80x83(III)
xe2x80x83wherein
R1 and X are as hereinbefore defined,
Yxe2x80x2 has the meanings given for Y hereinbefore with the proviso that any amino or imino group present is protected by a conventional protecting group, and
Axe2x80x2 denotes an ethynyl group, optionally followed by catalytic hydrogenation and/or cleaving of any protecting group used.
The reaction is preferably carried out in a solvent such as acetonitrile, diethylether, tetrahydrofuran or dimethylformamide in the presence of a palladium catalyst such as bis(triphenylphosphine)-palladium(II)chloride or tetrakis-(triphenylphosphine)-palladium(0) in the presence of a tertiary or inorganic base such as triethylamine, N-isopropyl-diethylamine, potassium-tert-butoxide, sodium carbonate or caesium carbonate and in the presence of a reaction accelerator such as a copper halide, e.g. copper(I)iodide and at temperatures between 20 and 120xc2x0 C., preferably at temperatures between 40 and 100xc2x0 C. (cf. also K. Sonogashira, Comprehensive Organic Synthesis, Vol. 3, page 52ff., Pergamon Press, Oxford 1991).
The protecting groups which may be used and their removal are described hereinafter (cf. also T. Greene, Protective Groups in Organic Synthesis, Wiley Interscience, New York 1981).
b. In order to prepare a compound of general formula I wherein the Arxe2x80x94A group contains a carboxy group and R5 is as hereinbefore defined or the Arxe2x80x94A group is as hereinbefore defined and R5 denotes an amino, amino-C1-3-alkyl, amidino or guanidino group or the Arxe2x80x94A group contains a carboxy group and R5 denotes an amino, amino-C1-3-alkyl, amidino or guanidino group:
converting a compound of general formula
Arxe2x80x2xe2x80x94Axe2x80x94HCR1xe2x80x94Xxe2x80x94Yxe2x80x3,xe2x80x83xe2x80x83(IV)
xe2x80x83wherein
A, R1, and X are as hereinbefore defined,
Arxe2x80x2 and Yxe2x80x3 have the meanings given for Ar and Y hereinbefore, with the proviso that
Arxe2x80x2 contains a group which can be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and Yxe2x80x3 has the meanings given for Y hereinbefore or
Arxe2x80x2 has the meanings given for Ar hereinbefore and Yxe2x80x3 contains a group which can be converted into an amino, amino-C1-3-alkyl, amidino or guanidino group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis, or
Arxe2x80x2 contains a group which can be converted into a carboxy group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis and Yxe2x80x3 contains a group which can be converted into an amino, amino-C1-3-alkyl, amidino or guanidino group by hydrolysis, treatment with an acid or base, thermolysis or hydrogenolysis,
is converted by hydrolysis, treatment with an acid or base, thernolysis or hydrogenolysis into a compound of general formula I wherein the Arxe2x80x94A group contains a carboxy group and R5 is as hereinbefore defined or the Arxe2x80x94A group is as hereinbefore defined and R5 denotes an amino, amino-C1-3-alkyl, amidino or guanidino group or the Arxe2x80x94A group contains a carboxy group and R5 denotes an amino, amino-C1-3-alkyl, amidino or guanidino group.
An example of a group which can be converted into a carboxy group might be a carboxyl group protected by a protecting group, for example, such as the functional derivatives thereof, e.g. the unsubstituted or substituted amides, esters, thioesters, trimethylsilylesters, orthoesters or iminoesters thereof which are conveniently converted into a carboxyl group by hydrolysis,
the esters thereof with tertiary alcohols, e.g. the tert-butylester, which are conveniently converted into a carboxyl group by treating with an acid or thermolysis, and
the esters thereof with aralkanols, e.g. the benzyl ester thereof, which are conveniently converted into a carboxyl group by hydrogenolysis.
The hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
If a compound of general formula IV contains the tert-butyl or tert-butyloxycarbonyl group, for example, this may also be cleaved by treating with an acid such as trifluoroacetic acid, formic acid, p-toluenesulphonic acid, sulphuric acid, hydrochloric acid, phosphoric acid or polyphosphoric acid, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, diethylether, tetrahydrofuran or dioxane, preferably at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between 0 and 60xc2x0 C., or also thermally, optionally in an inert solvent such as methylene chloride, chloroform, benzene, toluene, tetrahydrofuran or dioxane and preferably in the presence of a catalytic amount of an acid such as p-toluenesulphonic acid, sulphuric acid, phosphoric acid or polyphosphoric acid, preferably at the boiling temperature of the solvent used, e.g. at temperatures between 40 and 120xc2x0 C.
If a compound of general formula IV contains the benzyloxy or benzyloxycarbonyl group, for example, these may also be cleaved hydrogenolytically in the presence of a hydrogenation catalyst such as palladium/charcoal in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50xc2x0 C., e.g. at ambient temperature, and at a hydrogen pressure of 1 to 5 bar.
c. In order to prepare a compound of general formula I wherein R5 denotes an amidino group:
reacting a compound of general formula
Arxe2x80x94Axe2x80x94HCR1xe2x80x94Xxe2x80x94Yxe2x80x3,xe2x80x83xe2x80x83(V)
xe2x80x83optionally formed in the reaction mixture
xe2x80x83wherein
A, Ar, R1 and X are as hereinbefore defined and
Yxe2x80x3 denotes one of the groups mentioned for Y hereinbefore with the proviso that R5 denotes a Z1xe2x80x94(HNxe2x95x90)C-group wherein
Z1 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group,
xe2x80x83with an ammonium salt such as diammonium carbonate or ammonium acetate.
The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, tetrahydrofuran or dioxane at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 80xc2x0 C.
A compound of general formula V is obtained for example by reacting a corresponding cyano compound with a corresponding alcohol such as methanol, ethanol, n-propanol, isopropanol or benzyl alcohol in the presence of an acid such as hydrochloric acid or by reacting a corresponding amide with a trialkyloxonium salt such as triethyloxonium tetrafluoroborate in a solvent such as methylene chloride, tetrahydrofuran or dioxane at temperatures between 0 and 50xc2x0 C., but preferably at 20xc2x0 C., or a corresponding nitrile with hydrogen sulphide, conveniently in a solvent such as pyridine or dimethylformamide and in the presence of a base such as triethylamine and subsequently alkylating the thioamide formed with a corresponding alkyl or aralkyl halide.
In the reaction described above, a hydrogen halide may at the same time be added to an electron-rich or electron-poor triple bond.
d) In order to prepare a compound of general formula I wherein R5 denotes an amidino group which is substituted by a hydroxy group:
reacting a compound of general formula
Arxe2x80x94Axe2x80x94HCR1xe2x80x94Xxe2x80x94Yxe2x80x3,xe2x80x83xe2x80x83(V)
xe2x80x83optionally formed in the reaction mixture
xe2x80x83wherein
A, Ar, R1 and X are as hereinbefore defined and
Yxe2x80x3 denotes one of the groups mentioned for Y hereinbefore with the proviso that R5 denotes a Z1xe2x80x94(HNxe2x95x90)C group wherein
Z1 denotes an alkoxy or aralkoxy group such as the methoxy, ethoxy, n-propoxy, isopropoxy or benzyloxy group or an alkylthio or aralkylthio group such as the methylthio, ethylthio, n-propylthio or benzylthio group,
xe2x80x83with hydroxylamine or the salts thereof.
The reaction is conveniently carried out in a solvent such as methanol, ethanol, n-propanol, water, methanol/water, tetrahydrofuran, tetrahydrofuran/water, dioxane or dioxane/water in the presence of a base such as triethylamine at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 80xc2x0 C.
e. In order to prepare a compound of general formula I wherein X denotes an oxygen or sulphur atom, a carbonyl, imino or Nxe2x80x94(C1-3-alkyl)-imino group:
reacting a compound of general formula I
Arxe2x80x94Axe2x80x94HCR1xe2x80x94Z2,xe2x80x83xe2x80x83(VI)
xe2x80x83wherein
A, Ar and R1 are as hereinbefore defined and
Z2 denotes a leaving group such as a halogen atom or a sulphonyloxy group, e.g. a bromine or iodine atom, a methanesulphonyloxy or p-toluenesulphonyloxy group, with a compound of general formula
Uxe2x80x94Y,xe2x80x83xe2x80x83(VII)
xe2x80x83wherein
Y is as hereinbefore defined and
U denotes a hydroxy, mercapto, hydroxycarbonyl, imino or Nxe2x80x94(C1-3-alkyl)-imino group.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulphoxide or dimethylformamide optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20xc2x0 C. and the boiling temperature of the solvent used.
f. In order to prepare a compound of general formula I wherein Ar and/or Y contain a group which can be cleaved in vivo:
reacting a compound of general formula
Arxe2x80x3xe2x80x94Axe2x80x94HCR1xe2x80x94Xxe2x80x94Yxe2x80x2xe2x80x3,xe2x80x83xe2x80x83(VIII)
xe2x80x83wherein
A, R1, and X are as hereinbefore defined,
Arxe2x80x3 and Yxe2x80x2xe2x80x3 have the meanings given for Ar and Y hereinbefore, with the proviso that
Arxe2x80x3 contains a carboxy group and Yxe2x80x2xe2x80x3 has the meanings given for Y hereinbefore or Arxe2x80x3 has the meanings given for Ar hereinbefore and Yxe2x80x2xe2x80x3 contains an amino, amino-C1-3-alkyl, amidino or guanidino group or
Arxe2x80x3 contains a carboxy group and Yxe2x80x2xe2x80x3 contains a group which can be converted [into] an amino, amino-C1-3-alkyl, amidino or guanidino group,
xe2x80x83with a compound of general formula
Z3xe2x80x94R7,xe2x80x83xe2x80x83(IX)
xe2x80x83wherein
R7 denotes a C1-8-alkoxycarbonyl group, an Raxe2x80x94COxe2x80x94Oxe2x80x94(RbCRc)-group or the acyl group of one of the groups which can be cleaved in vivo as mentioned hereinbefore, whilst Ra to Rc are as hereinbefore defined, and
Z3 denotes a nucleofugic leaving group such as a halogen atom, e.g. a chlorine, bromine or iodine atom, or a p-nitrophenyl group or, if Arxe2x80x3 contains a carboxy group, Z may also denote a hydroxy group.
The reaction is preferably carried out in a solvent such as methanol, ethanol, methylene chloride, tetrahydrofuran, toluene, dioxane, dimethylsulphoxide or dimethylformamide optionally in the presence of an acid-activating or dehydrating agent and optionally in the presence of an inorganic or a tertiary organic base, preferably at temperatures between 20xc2x0 C. and the boiling temperature of the solvent used.
With a compound of general formula IX wherein Z3 denotes a nucleofugic leaving group, the reaction is preferably carried out in a solvent such as methylene chloride, acetonitrile, tetrahydrofuran, toluene, dimethylformamide or dimethylsulphoxide, optionally in the presence of a base such as sodium hydride, potassium carbonate, potassium tert-butoxide or N-ethyl-diisopropylamine at temperatures between 0 and 60xc2x0 C.
With a compound of general formula IX wherein Z3 denotes a hydroxy group, the reaction is optionally carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C.
If in a compound of general formula IX Z3 denotes a hydroxy group, the reaction may also be carried out with one of the reactive derivatives thereof, such as the esters, imidazolides or halides thereof, preferably in a solvent such as methylene chloride or ether and preferably in the presence of a tertiary organic base such as triethylamine, N-ethyl-diisopropylamine or N-methylmorpholine at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 50 and 100xc2x0 C.
If according to the invention a compound of general formula I is obtained wherein R5 denotes an amidino group, this may be converted by alkylation with a haloacetic derivative, by subsequent hydrolysis and decarboxylation into a corresponding amidino compound substituted by one or two methyl groups and/or
if a compound of general formula I is obtained wherein R5 denotes a hydroxyamidino group, this can be converted by catalytic hydrogenation into a corresponding amidino compound and/or
if a compound of general formula I is obtained which contains a double or triple bond, this can be converted by catalytic hydrogenation into a corresponding saturated compound and/or
if a compound of general formula I is obtained wherein X denotes a sulphur atom, this can be converted by oxidation into a corresponding sulphinyl or sulphonyl compound and/or
if a compound of general formula I is obtained wherein R2 denotes a tetra-hydropyrazolocarbonyl group, this can be converted by oxidation into a corresponding 4,5-dihydropyrazolocarbonyl compound and/or
if a compound of general formula I is obtained which contains a carbonyl group, this can be converted by a corresponding oxime into a corresponding oxime compound and/or
if a compound of general formula I is obtained which contains a carboxy group, this can be converted by an amine into a corresponding amide.
The subsequent alkylation is conveniently carried out in a solvent such as methylene chloride, tetrahydrofuran, dioxane, dimethylsulphoxide, dimethylformamide or acetone, optionally in the presence of a reaction accelerator such as sodium or potassium iodide and preferably in the presence of a base such as sodium carbonate or potassium carbonate or in the presence of a tertiary organic base such as N-ethyl-diisopropylamine or N-methylmorpholine, which may serve as the solvent at the same time, or optionally in the presence of silver carbonate or silver oxide at temperatures between xe2x88x9230 and 100xc2x0 C., but preferably at temperatures between xe2x88x9210 and 80xc2x0 C.
The subsequent hydrolysis is conveniently carried out either in the presence of an acid such as hydrochloric acid, sulphuric acid, phosphoric acid, acetic acid, trichloroacetic acid, trifluoroacetic acid or mixtures thereof or in the presence of a base such as lithium hydroxide, sodium hydroxide or potassium hydroxide in a suitable solvent such as water, water/methanol, water/ethanol, water/isopropanol, methanol, ethanol, water/tetrahydrofuran or water/dioxane.
The subsequent decarboxylation is carried out in the presence of an acid as hereinbefore described at temperatures between xe2x88x9210 and 120xc2x0 C., e.g. at temperatures between ambient temperature and the boiling temperature of the reaction mixture.
The subsequent catalytic hydrogenation is preferably carried out in the presence of a hydrogenation catalyst such as palladium/charcoal and in a suitable solvent such as methanol, ethanol, ethanol/water, glacial acetic acid, ethyl acetate, dioxane or dimethylformamide, preferably at temperatures between 0 and 50xc2x0 C., e.g. at ambient temperature, and at a hydrogen pressure of 1 to 5 bar.
The subsequent oxidation is preferably carried out in a solvent or mixture of solvents, e.g. in water, water/pyridine, acetone, methylene chloride, acetic acid, acetic acid/acetic anhydride, dilute sulphuric acid or trifluoroacetic acid, conveniently at temperatures between xe2x88x9280 and 100xc2x0 C. depending on the oxidising agent used.
In order to prepare a corresponding sulphinyl compound of general formula I the oxidation is conveniently carried out with one equivalent of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid, trifluoroacetic acid or formic acid at 0 to 20xc2x0 C. or in acetone at 0 to 60xc2x0 C., with a peracid such as performic acid in glacial acetic acid or trifluoroacetic acid at 0 to 50xc2x0 C. or with m-chloroperbenzoic acid in methylene chloride, chloroform or dioxane at xe2x88x9220 to 80xc2x0 C., with sodium metaperiodate in aqueous methanol or ethanol at xe2x88x9215 to 25xc2x0 C., with bromine in glacial acetic acid or aqueous acetic acid optionally in the presence of a weak base such as sodium acetate, with N-bromosuccinimide in ethanol, with tert-butylhypochlorite in methanol at xe2x88x9280 to xe2x88x9230xc2x0 C., with iodobenzodichloride in aqueous pyridine at 0 to 50xc2x0 C., with nitric acid in glacial acetic acid at 0 to 20xc2x0 C., with chromic acid in glacial acetic acid or in acetone at 0 to 20xc2x0 C. and with sulphuryl chloride in methylene chloride at xe2x88x9270xc2x0 C., and the resulting thioether-chlorine complex is conveniently hydrolysed with aqueous ethanol.
In order to prepare a sulphonyl compound of general formula I oxidation is carried out starting from a corresponding sulphinyl compound, conveniently with one or more equivalents of the oxidising agent used or starting from a corresponding sulphenyl compound conveniently with two or more equivalents of the oxidising agent used, e.g. with hydrogen peroxide in glacial acetic acid/acetic anhydride, trifluoroacetic acid or in formic acid at 20 to 100xc2x0 C. or in acetone at 0 to 60xc2x0 C., with a peracid such as performic acid or m-chloroperbenzoic acid in glacial acetic acid, trifluoroacetic acid, methylene chloride or chloroform at temperatures between 0 and 60xc2x0 C., with nitric acid in glacial acetic acid at 0 to 20xc2x0 C., with chromic acid, sodium periodate or potassium permanganate in acetic acid, water/sulphuric acid or in acetone at 0 to 20xc2x0 C.
In order to prepare a 4,5-dihydropyrazolocarbonyl compound of general formula I the oxidation may also be carried out using oxygen from the air in one of the above-mentioned solvents at ambient temperature.
The subsequent oxime formation is conveniently carried out in a solvent such as methanol/toluene in the presence of a dehydrating agent such as molecular sieves, preferably at the boiling temperature of the solvent used.
The subsequent amide formation is preferably carried out in a solvent or mixture of solvents such as methylene chloride, dimethylformamide, benzene, toluene, chlorobenzene, tetrahydrofuran, benzene/tetrahydrofuran or dioxane in the presence of a dehydrating agent, e.g. in the presence of isobutyl chloroformate, tetraethyl orthocarbonate, trimethyl orthoacetate, 2,2-dimethoxypropane, tetramethoxysilane, thionyl chloride, trimethylchlorosilane, phosphorus trichloride, phosphorus pentoxide, N,Nxe2x80x2-dicyclohexylcarbodiimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/N-hydroxysuccinimide, N,Nxe2x80x2-dicyclohexylcarbodiimide/1-hydroxybenzotriazole, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium tetrafluoroborate, 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium-tetrafluoroborate/1-hydroxy-benzotriazole, N,Nxe2x80x2-carbonyldiimidazole or triphenylphosphine/carbon tetrachloride, and optionally with the addition of a base such as pyridine, 4-dimethylaminopyridine, N-methylmorpholine or triethylamine, conveniently at temperatures between 0 and 150xc2x0 C., preferably at temperatures between 0 and 100xc2x0 C.
In the reactions described hereinbefore, any reactive groups present such as hydroxy, carboxy, amino, alkylamino or imino groups may be protected during the reaction by conventional protecting groups which are cleaved again after the reaction (cf. also T. Greene, Protective Groups in Organic Synthesis, Wiley Interscience, New York 1981).
For example, a protecting group for a hydroxy group may be a trimethylsilyl, acetyl, benzoyl, tert-butyl, trityl, benzyl or tetrahydropyranyl group,
protecting groups for a carboxy group may be a trimethylsilyl, methyl, ethyl, tertbutyl, benzyl or tetrahydropyranyl group and
protecting groups for an amino, alkylamino or imino group may be an acetyl, trifluoroacetyl, benzoyl, ethoxycarbonyl, tert-butoxycarbonyl, benzyloxycarbonyl, benzyl, methoxybenzyl or 2,4-dimethoxybenzyl group and additionally, for the amino group, a phthalyl group.
Any protecting group used is optionally subsequently cleaved for example by hydrolysis in an aqueous solvent, e.g. in water, isopropanol/water, acetic acid/water, tetrahydrofuran/water or dioxane/water, in the presence of an acid such as trifluoroacetic acid, hydrochloric acid or sulphuric acid or in the presence of an alkali metal base such as lithium hydroxide, sodium hydroxide or potassium hydroxide or by ether splitting, e.g. in the presence of iodotrimethylsilane, at temperatures between 0 and 100xc2x0 C., preferably at temperatures between 10 and 50xc2x0 C.
However, a benzyl, methoxybenzyl or benzyloxycarbonyl group is cleaved, for example, hydrogenolytically, e.g. with hydrogen in the presence of a catalyst such as palladium/charcoal in a solvent such as methanol, ethanol, ethyl acetate, dimethylformamide, dimethylformamide/acetone or glacial acetic acid optionally with the addition of an acid such as hydrochloric acid at temperatures between 0 and 50xc2x0 C., but preferably at ambient temperature, and at a hydrogen pressure of 1 to 7 bar, but preferably 3 to 5 bar.
A tert-butyl or tert-butyloxycarbonyl group is preferably cleaved by treating with an acid such as trifluoroacetic acid or hydrochloric acid, optionally using a solvent such as water, methylene chloride, diethylether, tetrahydrofuran or dioxane.
An allyloxycarbonyl group is cleaved by treating with a catalytic amount of tetrakis-(triphenylphosphine)-palladium(O), preferably in a solvent such as tetrahydrofuran and preferably in the presence of an excess of a base such as morpholine or 1,3-dimedone at temperatures between 0 and 100xc2x0 C., preferably at ambient temperature and under inert gas, or by treating with a catalytic amount of tris-(triphenylphosphine)-rhodium(I)chloride in a solvent such as aqueous ethanol and optionally in the presence of a base such as 1,4-diazabicyclo[2.2.2]octane at temperatures between 20 and 70xc2x0 C.
The compounds of general formulae II to IX used as starting materials, some of which are known from the literature, are obtained by methods known from the literature and their preparation is also described in the Examples.
Thus, for example, a compound of general formula II is obtained by reacting a corresponding substituted halobenzene with a corresponding compound,
a compound of general formula III is obtained by reacting a corresponding aniline with a propargyl halide and subsequently converting the substituted aniline thus obtained into a compound of general formula III by known methods, e.g. by Pinner reaction, and
the compounds of general formulae IV, V, VI and VIII are conveniently obtained by conventional methods as described in the present invention.
Moreover, the compounds of general formula I obtained may be resolved into their enantiomers and/or diastereomers, and the compounds of general formula I obtained which contain a double bond may be resolved into their cis/trans isomers.
Thus, for example, the compounds of general formula I obtained which occur as racemates may be separated by methods known per se (cf. Allinger N. L. and Eliel E. L. in xe2x80x9cTopics in Stereochemistryxe2x80x9d, Vol. 6, Wiley Interscience, 1971) into their optical enantiomers and compounds of general formula I with at least 2 asymmetric carbon atoms may be resolved into their diastereomers on the basis of their physical-chemical differences using methods known per se, e.g. by chromatography and/or fractional crystallisation, and, if these compounds are obtained in racemic form, they may subsequently be resolved into the enantiomers as mentioned above.
The enantiomers are preferably separated by column separation on chiral phases or by recrystallisation from an optically active solvent or by reacting with an optically active substance which forms salts or derivatives such as e.g. esters or amides with the racemic compound, particularly acids and the activated derivatives or alcohols thereof, and separating the diastereomeric mixture of salts or derivatives thus obtained, e.g. on the basis of their differences in solubility, whilst the free antipodes may be released from the pure diastereomeric salts or derivatives by the action of suitable agents. Optically active acids in common use are e.g. the D- and L-forms of tartaric acid or dibenzoyltartaric acid, di-o-tolyltartaric acid, malic acid, mandelic acid, camphorsulphonic acid, glutamic acid, aspartic acid or quinic acid. An optically active alcohol may be for example (+) or (xe2x88x92)-menthol and an optically active acyl group in amides, for example, may be a (+)- or (xe2x88x92)-menthyloxycarbonyl.
Furthermore, the compounds of formula I may be converted into the salts thereof, particularly for pharmaceutical use into the physiologically acceptable salts with inorganic or organic acids. Acids which may be used for this purpose include for example hydrochloric acid, hydrobromic acid, sulphuric acid, methanesulphonicacid, phosphoric acid, fumaric acid, succinic acid, lactic acid, citric acid, tartaric acid or maleic acid.
Moreover, if the new compounds of formula I contain a carboxy group, they may subsequently, if desired, be converted into the salts thereof with inorganic or organic bases, particularly for pharmaceutical use into the physiologically acceptable salts thereof. Suitable bases for this purpose include for example sodium hydroxide, potassium hydroxide, cyclohexylamine, ethanolamine, diethanolamine and triethanolamine.
As already mentioned, the new compounds of general formula I and the salts thereof have valuable properties.
Thus, the compounds of general formula I wherein Y does not contain a cyano group have valuable pharmacological properties, particularly an antithrombotic activity which is preferably based on an effect on thrombin or factor Xa, for example on a prolonging effect on aPTT time and on an inhibitory effect on related serine proteases such as e.g. trypsin, urokinase factor VIIa, factor IX, factor XI and factor XII, and the compounds of general formula I wherein Y contains a cyano group are valuable intermediate products for preparing the compounds of general formula I wherein R5 denotes an optionally substituted aminomethyl, amidino or guanidinomethyl group.
For example, the compounds
A=rac-4-{3-[5-ethoxycarbonylmethyl-2-methyl-4-(2-methyl-pyrrolidinocarbonyl)-phenyl]-propargylamino}benzamidine,
B=rac-4-{3-[2,5-dimethyl-4-(2-methyl-pyrrolidinocarbonyl)-phenyl]-propargylamino}benzamidine,
C=4-[3-(2,5-dimethyl-4-isopropylcarbonyl-phenyl)propargyl-amino]benzamidine,
D=4-{3-[2,5-dimethyl-4-(N-methyl-N-pyridin-2-yl-aminocarbonyl)-phenyl]propargylamino}benzamidine,
E=4-{3-[2,5-dimethyl-4-(N-methyl-N-pyridin-2-yl-aminocarbonyl)-phenyl]prop-1-ylamino}benzamidine,
F=4-[3-(3-methyl-4-pyrrolidinocarbonyl-phenyl)-propargyl-amino]-benzamidine,
G=4-{3-[2,5-dimethyl-4-(N-(2-methoxycarbonyl-ethyl)-N-ethyl-carbonylamino)-phenyl]-propargylamino}benzamidine,
H=4-{3-[2,5-dimethyl-4-(N-isopropyl-N-hydroxycarbonylmethyl-aminocarbonyl-amino)-phenyl]-propargylamino}-benzamidine and
I=4-{3-[2,5-dimethyl-4-(N-isopropyl-N-hydroxycarbonylmethyl-carbonyl-amino)-phenyl]-propargylamino}-benzamidine
were investigated for their effect on prolonging the aPTT time as follows:
Materials:
plasma, from human citrated blood.
PTT reagent, Boehringer Mannheim (524298), Calcium solution (0.025 mol/l), Behring Werke, Marburg (ORH 056/57),
Diethylbarbiturate acetate buffer, Behring Werke, Marburg (ORWH 60/61),
Biomatic B10 coagulometer, Desaga, Wiesloch.
Method:
The aPTT time was determined using a Biomatic B10 coagulometer made by Messrs. Sarstedt.
The test substance was placed in the test tubes prescribed by the manufacturer with 0.1 ml of human citrated plasma and 0.1 ml of PTT reagent. The mixture was incubated for three minutes at 37xc2x0 C. The clotting reaction was started by the addition of 0.1 ml of calcium solution. The time is measured using the apparatus from the addition of the calcium solution up to the clotting of the mixture. Mixtures to which 0.1 ml of DBA buffer were added were used as the controls.
According to the definition, a dosage-activity curve was used to determine the effective concentration of the substance at which the aPTT time is double compared with the control.
The Table which follows contains the results found:
In view of their pharmacological properties the new compounds and the physiologically acceptable salts thereof are suitable for the prevention and treatment of venous and arterial thrombotic diseases, such as for example the treatment of deep leg vein thrombosis, for preventing reocclusions after bypass operations or angioplasty (PT(C)A), and occlusion in peripheral arterial diseases such as pulmonary embolism, disseminated intravascular coagulation, for preventing coronary thrombosis, stroke and the occlusion of shunts. In addition, the compounds according to the invention are suitable for antithrombotic support in thrombolytic treatment, such as for example with rt-PA or streptokinase, for preventing long-term restenosis after PT(C)A, for preventing metastasis and the growth of clot-dependent tumours and fibrin-dependent inflammatory processes.
The dosage required to achieve such an effect is appropriately 0.1 to 30 mg/kg, preferably 0.3 to 10 mg/kg by intravenous route, and 0.1 to 50 mg/kg, preferably 0.3 to 30 mg/kg by oral route, in each case administered 1 to 4 times a day. For this purpose, the compounds of formula I prepared according to the invention may be formulated, optionally together with other active substances, with one or more inert conventional carriers and/or diluents, e.g. with corn starch, lactose, glucose, microcrystalline cellulose, magnesium stearate, polyvinylpyrrolidone, citric acid, tartaric acid, water, water/ethanol, water/glycerol, water/sorbitol, water/polyethyleneglycol, propyleneglycol, cetyl stearyl alcohol, carboxymethylcellulose or fatty substances such as hard fat or suitable mixtures thereof, to produce conventional galenic preparations such as plain or coated tablets, capsules, powders, suspensions or suppositories.